Diltiazem, a well known drug with calcium antagonist activity has the formula (I) ##STR2##
As seen in formula (I), Dilitiazem has two asymmetric carbon atoms (marked with (*)), the configuration of Dilitiazem at its two asymmetric carbons being (2S, 3S).
Numerous methods are known for the synthesis of Dilitiazem from the intermediate threo-propionic acid, and particularly from the optical isomer D(+)-threo-propionic acid.
Several methods have been proposed for the optical resolution of (.+-.) threo-propionic acid (II). Thus, U.S. Pat. No. 4,416,819, JP 103,356 and EP 381,570 describe the use of D(+)-phenylethylamine as the resolving agent for (.+-.)-threopropionic acid.
Other optically active amines such as tolylethylamine (JP 097,606), R(+)-naphtylethylamine (JP 61,207,371) or threo-1-(4-X-phenyl)-2-amino-1,3-propanediol (EP 89,113,135) were also used for the same purpose, while in accordance with JP 8,822,556, IT 023,769 and WO 9100270 L-lysine or phenyl-glycine amide were used instead of the optically active amines as resolving agents.
JP 8,910,617 describes the resolution (.+-.) of erythro-propionic acid by selective hydrolysis of its methyl ester. In this procedure, purification of the separated isomer is necessary, resulting in a reduced yield.
None of the above methods have been found satisfactory, because of low yields, difficult reaction conditions and/or poor recovery of the expensive catalyst or resolving agent.